Synthesis of monofluoroalkenes through selective hydrodefluorination of gem-difluoroalkenes with Red-Al®

Abstract

A novel and practical approach for the selective hydrodefluorination of gem-difluoroalkenes using Red-Al® as a reductant at room temperature in CH₂Cl₂ without any additional base and metal catalyst was reported. Various monofluoroalkenes were obtained in moderate to high yields with good E-selectivity.

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The monofluoroalkenes are an important class of fluorinated compounds and have potential applications in medicinal chemistry and material sciences.¹ Meanwhile, they can be used as fluorinated building blocks for further transformation in organic syntheses.² Nowadays, various methods for the preparation of monofluoroalkenes have therefore been developed,³ including reductive defluorination of allylic gem-difluorides with a Pd catalyst,^4a gold-catalyzed hydrofluorination of alkynes in the presence of Et₃N·3HF,^4b fluorination of alkenylboronic acid^4c and Julia–Kocienski fluoroolefination reaction with various ketones and aldehydes.^4d

Hydrodefluorination (HDF) is the simplest transformation of C–F bond.⁵ Selective hydrodefluorination of polyfluorinated compounds has become a useful approach to access partially fluorinated compounds which are difficult to obtain otherwise.⁶ However, most research focused on the catalytic selective hydrodefluorination of fluoroarenes, the selective hydrodefluorination of fluoroalkenes have remained rare.⁷ In particular, only few examples referring to the transformation of difluoroalkene derivatives to the corresponding monofluoroalkenes have been observed.⁸ Xiao and Hong have reported the preparation of 2-fluorovinyl tosylate by treating 2,2-difluorovinyl tosylate with LiAlH₄ in ether.^8a Shi has described that the reductive reaction of 2-[(trimethylsilyl)methyl]-substituted 3,3-difluoropropenoate with LiAlH₄ led exclusively to the formation of the Z-configurated monofluorinated allylic (only one example),^8b whereas the reaction of LiAlH₄ with a simple 2-alkyl-substituted 3,3-difluoropropenoate reported by Watanabe gave monofluoroallylic alcohols with little stereoselectivity.^8c

Recently, Paquin and coworkers developed two novel methods for the synthesis of β-fluorostyrene and 1,1-diaryl-2-fluoroethenes respectively.⁹ In both pathways, a common intermediate (Z)-1-aryl-2-fluoro-1-(trimethylsilyl)ethene was generated via an addition/elimination reaction of lithium triethylhydridoborate (LiEt₃BH) to silylated β,β-difluorostyrene derivative. Furthermore, Red-Al® (NaAlH₂(OCH₂CH₂OCH₃)₂) was also used as a reducing agent for the conversion of difluoroalkenes to monofluoroalkenes.¹⁰ However, these methods suffer from several drawbacks, such as narrow substrate scope, low stereoselectivity, lack generality, over reduction and the use of environmentally unfriendly solvent such as benzene and toluene. Consequently, the development of the synthesis of monofluoroalkenes via the selective reduction of common difluoroalkenes under mild reaction conditions is highly desirable. Herein, we report an efficient and practical approach for the monofluoroalkenes via the hydrodefluorination of difluoroalkenes using Red-Al® as reductant at room temperature in CH₂Cl₂ without any added base and metal catalyst (Scheme 1).

Scheme 1 Selective hydrodefluorination of gem-difluoroalkenes with Red-Al®.

As part of our continued interest in the C–F bond of organofluorine compounds,¹¹ in this communication, we focused on the selective reductive cleavage of sp² C–F bonds of gem-difluoroalkenes. Initially, we used 1-(2,2-difluorovinyl)-4-methoxy-benzene 1a as the model substrate to examine the reduction activities of various reducing agents (Table 1, entries 1–8). Among the reducing agents tested, LiAlH₄, LiEt₃BH and Red-Al® promoted the reaction much more efficiently and gave a mixture of monofluoro product 2a and over-reduction product 3a in high yields but with poor selectivity (entries 6–8). It is reported that Red-Al® is a safer substitute for LiAlH₄ and LiEt₃BH,¹² therefore, we chose Red-Al® as the reductant for further optimization of reaction conditions.

Table 1 Selective hydrodefluorination of 2,2-difluoroalkenes under different conditions^a

Entry	Reducing agent (equiv.)	Solvent	Temp. (°C)	Time (h)	Yield^b (%) (2a/3a)
a Reaction condition: 1a (1.0 mmol), solvent (8 mL).b Yields determined by GC analysis.
1	NaH (4.0)	THF	60	4	N.R.
2	NaBH4 (4.0)	THF	60	4	N.R.
3	Bu3SnH (4.0)	THF	60	4	N.R.
4	LiAl(O-t-C4H9)3 (4.0)	THF	60	4	N.R.
5	DIBAL-H (4.0)	THF	60	4	12/0
6	LiEt3BH (4.0)	THF	60	4	58/42
7	LiAlH4 (2.0)	THF	60	4	81/5
8	Red Al® (2.8)	THF	60	4	87/13
9	Red Al® (4.0)	THF	60	4	68/32
10	Red Al® (8.0)	THF	60	4	35/65
11	Red Al® (2.8)	THF	R.T.	1	95/5
12	Red Al® (2.8)	Et2O	R.T.	1	97/3
13	Red Al® (2.8)	Toluene	R.T.	1	95/5
14	Red Al® (2.8)	Benzene	R.T.	1	97/3
15	Red Al® (2.8)	CH2Cl2	R.T.	1	99/1
16	Red Al® (2.0)	CH2Cl2	R.T.	1	94/0
17	Red Al® (1.4)	CH2Cl2	R.T.	1	89/0

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The reaction results were significantly affected by the amount of Red-Al®. The use of 2.8 equiv. of Red-Al® could provide monofluoroalkene 2a as major product along with small amount of 1-methoxy-4-vinylbenzene 3a (entry 8). However, when the amount of Red-Al® was increased to 4.0 or 8.0 equiv., the yields of 2a decreased dramatically (entries 9 and 10). Interestingly, attempts to further improve the yield of 3a by using large amount of Red-Al® were unsuccessful.

To our delight, when the reaction was performed at room temperature within 1 hour, the desired product 2a was obtained in higher yield and the amount of over-reduction product 3a decreased obviously (entry 8 vs. entry 11). Further screening of the solvent showed that Et₂O, toluene, benzene and CH₂Cl₂ were also suitable for this transformation (entries 12–15). However, when THF, Et₂O, toluene and benzene were used as solvents, the yield of byproduct 3a would increase after a prolonged reaction time, whereas CH₂Cl₂ still afforded the monofluoro product 2a in excellent yield with high E-selectivity (entry 15). Considering the generality, toxicity and volatility of solvent, CH₂Cl₂ was the most suitable solvent for this reaction.

In addition, the reaction proceeded less efficiently when the amount of Red-Al® was decreased to 2.0 or 1.4 equiv. (entries 16 and 17).

Having established the optimized method (Table 1, entry 15), we next probe the generality and scope of this hydrodefluorination reaction of different gem-difluoroalkenes with Red-Al® (Table 2). All the gem-difluoroalkenes (1a–n) were prepared according to the reported procedure.¹³ It was found that difluoroethenes with strong electron-donating substituents on the aromatic ring afforded the corresponding E-monofluoro products 2a–j in good to high yields (more than 96%, GC/MS) and good stereoselectivity. 1-(2,2-Difluorovinyl) naphthalene (1m) and 4-(2,2-difluorovinyl)-1,1′-biphenyl (1n) were also good substrates for this reduction reaction. When difluoroethenes with weak electron-withdrawing substituent on the aromatic ring such as 1-chloro-4-(2,2-difluorovinyl)benzene (1k) and 1-bromo-3-(2,2-difluorovinyl)benzene (1l) were used as substrates, the reaction also proceeded smoothly. Unfortunately, (E)-isomers could not be separated from the corresponding (Z)-isomers due to their similarity in affinity to chromatographic silica gel.

Table 2 Selective hydrodefluorination of various gem-difluoroalkenes^a,b,c

a Reaction condition: gem-difluoroalkenes (1.0 mmol), Red-Al® (2.8 mmol), CH₂Cl₂ (8 mL), 25 °C.b Isolated yield.c The E/Z selectivity were determined by ¹⁹F NMR.d The reaction was completed within 15–20 minutes.

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Finally, symmetrical gem-difluoroalkenes 1o–q were also compatible with the reaction conditions and gave the monofluoro products 2o–q in good yields (Table 3). The symmetrical gem-difluoroalkenes (1o–q) were prepared according to the reported procedure.¹⁴

Table 3 Selective hydrodefluorination of symmetrical gem-difluoroalkenes^a,b

a Reaction condition: symmetrical gem-difluoroalkenes (1.0 mmol), Red-Al® (2.8 mmol), CH₂Cl₂ (8 mL), 25 °C.b Isolated yield.c The reaction was completed within 5 minutes.

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On the basis of the above results and literatures,¹⁵ we tentatively suggest a plausible mechanism (Scheme 2). In the first step, addition of negative hydrogen ion (H⁻) originated from Red-Al® to gem-difluoroalkene would result in the formation of the key carbanion intermediate I. Subsequently, rotation of the intermediate I by ±60 degrees would generate two conformations, II and III. The conformation III is unstable due to electronic repulsion between the aryl group and fluorine atom. Finally, the elimination of a fluoride ion from the preferred conformation II affords (E)-isomer as the major product.

Scheme 2 A plausible mechanism.

In summary, we have developed a novel and highly efficient method for the selective reduction of difluoroalkenes with Red-Al® in CH₂Cl₂ under mild conditions. The monofluoro products were obtained in moderate to high yields with high E-selectivity. Compared with the previously reported methods,¹⁰ the protocol developed in this communication has some obvious synthetic advantages such as the use of relative green solvent (CH₂Cl₂ vs. benzene), performing the reaction under mild condition (room temperature vs. reflux), the high stereoselectivity (9 : 1 vs. 3 : 1) and the broad substrate scope. Furthermore, no over-reduction products were observed even after a prolonged reaction time. The protocol reported herein provided a practical access to a variety of different monofluoroalkenes.

Acknowledgements

We are grateful for financial supports from the National Natural Science Foundation of China (Grant no. 21302128, 21272070).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra04221f

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